Project Summary/Abstract Studies of visual working memory, the process of maintenance and manipulation of information during goal directed behaviors, often involve comparisons of visual stimuli across time and space. Such tasks require subjects to identify these stimuli, retain them in memory and retrieve them at the time of comparison. Thus, the circuitry underlying such tasks must involve cortical regions sub-serving sensory processing, maintenance, attention and decision-making. For our studies of visual working memory we chose tasks involving memory-guided comparisons of visual motion since the neural code of this dimension and the cortical areas involved in its processing have been examined in some detail. For that reason, we focused on two reciprocally interconnected regions, the area playing a key role in processing of visual motion, area MT, and the lateral prefrontal cortex (LPFC), linked to attention, memory and executive control. Our lesion and single cell recording studies linked both areas to the ability to remember visual motion. Specifically, the damage of either LPFC or MT resulted in deficits in remembering visual motion. Furthermore, recording studies revealed motion signals in the LPFC likely to be supplied by MT and memory and comparison signals in MT likely to reflect influences from LPFC neurons. We hypothesize that the content and the dynamics of memory-related activity in MT and LPFC is a product of the interactions between neurons in the two areas during which they process and exchange motion signals generated during the task. In this renewal application we will address this hypothesis directly by simultaneously recording activity of multiple neurons in both areas, with the focus on memory-related signals represented in each area and on dynamic interactions between them during comparisons of directions of two moving stimuli separated by a delay. In our analysis we will focus on the nature of activity recorded simultaneously from multiple MT and LPFC neurons during the memory delay and during the comparison phase of the task and examine the interactions between neurons in the two areas (Aim 1). We will also reversibly inactivate localized sites in the LPFC, to examine LPFC influences on memory-related activity recorded in area MT during working memory tasks (Aim 2). To reveal the nature of memory-related signals and their interactions in the two areas we will focus on the memory delay and the comparison stage of the task. We will examine activity of simultaneously recorded neurons in each area on a trial-by-trial basis, apply population decoding algorithms, examine inter-neuronal and inter-areal noise correlations and synchrony while manipulating stimulus locations and task demands. The focus on the activity of simultaneously recorded neurons across the MT-LPFC network represents an important shift of emphasis from individual neurons to a more synergistic view of cortical function. This change of focus and the use of state-of-the-art techniques will allow us to identify network dynamics and codes that underlie memory and comparison processes during motion direction discrimination tasks.